Targeting mechanisms of radiation resistance

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

This project is now heavily focused on using samples from clinical trials to identify molecular mechanisms of resistance to radiation. This approach has evolved as we have collected tumor tissue and clinical outcomes data from prostate cancer patients on my protocol, 13-C-0119. This clinical trial is allowing us to evaluate multiple biologic, clinical, and radiographic predictors of local failure in patients treated with radiotherapy for localized prostate cancer. Patients enrolled in this study undergo a pretreatment multiparametric MRI and MRI-guided research biopsy of all tumors within their prostate. Following radiation therapy, patients with a rising PSA who meet biochemical failure criteria undergo repeat multiparametric MRI of the prostate and repeat MRI-guided research biopsy of persistent tumor. The molecular characteristics of tumor are analyzed to evaluate for predictors of failure and to study tumor evolution after radiation. To date, the laboratory and or collaborators have identified that a transcriptional signature of TGF-beta activation in pretreatment tumor biopsies predicts for biochemical recurrence. A gene signature has been developed and validated in multiple external datasets of men undergoing radiotherapy with or without androgen deprivation therapy for prostate cancer. During this past year, the laboratory has continued to work to analyze matched pretreatment and time of recurrence samples in men treated with external beam radiotherapy for prostate cancer. These findings, as well as those from our prospective cohort described above, are further investigated. Laboratory studies are ongoing to identify if specific components of pathways correlated with recurrence in pretreat tumor biopsies can be targeted to enhance radiation response. Further, patient derived xenografts of radiorecurrent cancer are being developed as a component of this work, a resource that does not currently exist elsewhere. Data from the tissue studies described above are continuing to be mined to generate a list of candidate pathway responsible for radiation resistance in prostate cancer. These data will inform laboratory studies aimed at determining the importance of these pathways in radiation response. Similarly, these molecules are being evaluated in blood collected across numerous trials to determine if they have prognostic or predictive utility. These efforts are being conducted in many different timepoints along the prostate cancer continuum, including before treatment of men with prostate cancer, at the time of biochemical recurrence after definitive radiation, at the time of biochemical recurrence after surgical treatment, and at the time of biochemical recurrence after post-operative radiation. The project has also included a number of clinical trials geared towards developing treatments for men with recurrent prostate cancer after prior radiation or surgery. This has included the development and complete accrual to two clinical trials in this patient population. Final results of both trials are now available.